PROJECT SUMMARY/ABSTRACT Aging is an emerging problem in chronic treated HIV-1. Despite potent antiretroviral therapy (ART), those aging with HIV are at an increased risk of functional decline and death compared with the general aging population, due to a higher inflammation and comorbidity burden such as cardiovascular disease (CVD). Mechanisms of aging in HIV+ adults must be identified so that therapies can be developed to lessen its impact. Dysregulation of the immune system contributes to aging and increases morbidity and mortality in HIV infection. Aging of the immune system (immune senescence) is an area of critical need for research related to mechanisms of HIV related aging. Aged monocytes/macrophages (M/M) and T-cells are associated with comorbidities such as CVD. T cell senescence has been inconsistently associated with HIV-morbidity. However, there is limited data regarding M/M senescence and molecular signatures of cellular senescence in T cells and M/M in chronic treated HIV-infection. Given the role of immune senescence in HIV-related morbidity and mortality in chronic treated HIV infection, studying molecular signatures of cellular senescence in T cells and M/M may identify new targets for therapeutic intervention. The MACS is an ongoing study of the history of HIV infection that includes >7000 HIV+ and demographically similar HIV- men who have sex with men (MSM) with dataset on aging and its phenotypes. Using the platform of the MACS, this proposal will establish the role of molecular signatures of cellular senescence [senescence-associated beta-galactosidase (SA-?-gal), ?H2AX, p16 (INK4a)] in M/M and T cells in the setting of HIV-related aging. Identifying molecular targets for therapeutic intervention may reduce the excess morbidity and mortality remaining despite ART in HIV-1 infected aged persons. This work is innovative, has a potential impact on public health and directly addresses HIV research priorities regarding HIV-associated comorbidities.